Project Summary This project is motivated by the preliminary finding that in isolated pig hearts, the process by which the first organized beats of ventricular fibrillation (VF) break down into fully-developed VF begins at the anterior junction of the right and left ventricles. The broad objectives of the proposed research are to determine the mechanisms of this initial breakdown and to test interventions that might prevent it. The phenomenon will be studied in normal swine hearts, in swine hearts with healed infarcts and pacing-induced cardiomyopathy, and in myopathic human hearts. The long-term goal is to prevent sudden cardiac death secondary to VF. Specific Aim 1. In normal hearts, determine how the first rotors formed at the onset of VF fragment into multiple new rotors. A number of questions will be addressed to determine the mechanisms of this initial breakup: (1) Does the site of the first propagation failure have an intrinsically prolonged action potential duration (APD) relative to surrounding tissue? (2) Is there APD alternans (long-short alternation) at the breakup site with propagation failing on the long cycle? (3) If so, is the alternans spatially discordant (neighboring regions on opposite phases of the long-short alternation), and does propagation failure occur at the boundary between these regions? (4) Are there geometric or structural factors that increase the load on propagating wavefronts and predispose them to local failure? This aim will employ optical mapping of the entire epicardial surface of intact isolated pig hearts and simultaneous epi- and endocardial optical mapping of isolated pig hearts that have been cut open to allow optical access to the endocardium. Specific Aim 2. Determine if the transition to VF begins in the same consistent location in diseased hearts as in normal hearts. Mapping studies will be performed in diseased hearts reflective of the population at high risk for sudden cardiac death. Preparations will include swine hearts with pacing induced nonischemic dilated cardiomyopathy, swine hearts with healed infarcts, and myopathic human hearts (ischemic and nonischemic) explanted from transplant recipients. Our primary goal for these studies will be to determine if the first wavebreak in the transition to VF occurs in the same consistent location as in normal hearts. Specific Aim 3. Determine if the transition to VF can be delayed or suppressed by local interventions at the site of the first new wavebreaks. Interventions we will test include rapid pacing at the site of breakup to prevent influx of wavefronts generated by the initial rotor(s), local application of agents to shorten recovery at the breakup site, local heating, and ablation lesions. Success of this aim could potentially lead to new anti-VF therapies or devices. This aim will use optical mapping of both normal and diseased hearts.